Aminospiro[3. 3] heptane derivatives



hydride. w

United States Patent 3,168,564 AMINGSPZROBQHETTANE DERIVATTVES Leslie G. Htnnber, Montreal, Quebec, Canada, assignor to American Home Froducts Corporation, New York, N.Y., a corporation oi Delaware No Drawing. Filed Mar. 12, 1963, Scr. No. 264,722

1 3 Claims. ((11. 269-5765) This invention relates to novel chemical compounds, certain new derivatives at spiro[3.3]heptane and to the process utilized in their preparation. More particularly my invention relates to aralkylaminoallcyl and substituted aralkylaminoalkyl derivatives of spiro[3.3]heptane, which new chemical compounds possess valuable pharmacological properties.

The new chemical compounds, in base form, may be generically represented by the Formula I wherein R represents aryl or substituted aryl.

The novel chemical compounds possessing interesting biological activities, in base form, are thus 2,5-bis(aralkyl or substituted arallcylaminomethyl)-spiro[3.3]heptanes. These compounds, being basic in nature, form tertiary acid addition salts. Such acid addition salts with pharmacologically acceptable acids are biologically equivalent to 'the free bases, and constitute a preferred form for the administration of the compounds of my invention.

The new chemical compounds forming the subject of this invention are useful as agents for lowering cholesterol levels in the blood. For example, Compound I, wherein R is orthochlorophenyl, will lower the cholesterol blood level in the intact rat by up to 45% when administered 3,168,554 Patented Feb. 2, 1965 This process may be indicated schematically as follows:

NHa [H] I 3(0001), 13(CONH lB(CH NHg);

l R-CHO in which B represents the divalent spiro[3.3]heptyl group, with the two substituents attached in the 2,5 positions', R represents phenyl or substituted phenyl; and HA represents a pharmacologically acceptable acid.

The following examples illustrate my invention further.

EXAMPLE 1 Spiro[3 .3 1hepfane-ZJ-dicarboxamide Spiro[3.3]heptane 2,5 dicarbonylchloride (6.0 gm.)

. was added slowly to aqueous cone. ammonium hydroxide rally at a dose of 75 micromoles per kilogram of body weight.

My preferred procedure for preparing the new chemical compounds may be described as follows: Spiro[3.3]heptane-2,5-dicarbonylchloride, a compound previously described by Backer and Schurnik, Rec. Trav.

Chirn, 5 0, 921 (1931), is reacted with aqueous COHC$I1-.

trated ammonia, preferably at low temperature. The re suiting diamide, spiro[3.3]heptane-2,5-dicarboxamide, is

' hydride (1.0 gm), to yield 2,5-bis(o-chlorobenzylaminohours at room temperature.

(60 ml.) at Ill-15 C. The mixture was stirred for 3 The resulting compound, spiro{3.3]heptane 2,5 dicarboxamide, was filtered off, washed with water and dried. It had a melting point of 252-259 C. In the infra-red spectrum it had bands at 3410 cmr 3220 cm. and 1650 cmf EXAMPLE 2 2,5 -bis(am inom elhyl) spiro [3-3 heptane EXAMPLE 3 2,5 -bi s(0-chlorobenzylaminomethyl) -spir0[3,3]heptane The bisaminomethylspiroheptane described in Example 2 was condensed with twoequivalents of o-chlorobenzaldehyde to yield the corresponding Schiii base. It was reduced directly in methanol solution with sodiumboro- I methyl)-spiro[3.3]heptane; A max. 265 mu e=46 1) reduced, preferably with lithium aluminum hydride in refluxing tetrahydrofuran, to '2,S-bisaminomethyl-spiro- {3.31heptane. The .bisaminomethyl derivative of spire-f [3.3jheptane is caused .to react with a suitable benzaldehyde or substituted benzaldehyde and removing twomole cules of water from the reaction mixture. The resulting benzylidine, or substituted benzylidine, derivative (a Schiif j base) maythen be reduced to thecorresponding secondaryfamino derivativeby treatment with a reducing agent,

such as, for example, by treatment with. sodium borohyplatinum oxide; or lithium aluminum dride; hydrogen and The free base is then recovered, preferably by evapo- Y ration off of the solvent. The resultant product may then be converted to asuitable acid addition salt by conven tional means, asby treatment with a pharmacologically acceptable acid. For example, the hydrochloride salts may bereadil'yobtained by treatment of the base'with hydrogen chloridefin ether solution. i i

A dihydrochloride salt was prepared by treatment of the base-With hydrogen chloride in ether solution. It cryspoint of 224--230 C.

1tallized from a methanohether mixture and had a melting Analysis confirmed the empirical formula Cg H N Clgf for the dihydro'chloride salt.

v 1. A compound selected from the group which consistsf of 2,5-bis o-hlorobenzylaminomethyl) -spiro [3 .3 heptane and its dihydrochloride salt.

heptane. w v

"3. The dihydrochlor-ide salt of. 2,5-bis(o-ch1oroben zyl- 2. 2,5 -bis(o chlorobenaylaminomethyl)-spiro[3.3]-

. aminomethyl) spiroi3.3]heptane.

References Cited iirthe file of this patent UNITED STATES BATENTS 1 p I 1 OTHER, REFERENCES {Rice etfal;

Jourii. Orgn. Chem.,?vo1. 26, 15 54-58. 

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF 2,5-BIS(O-CHLOROBENZYLAMINOMETHYL)-SPIRO(3.3)HEPTANE AND ITS DIHYDROCHLORIDE SALT. 